Efavirenz is a non-nucleoside reverse transcriptase inhibitor, developed by Merck, the chemical name of which is (S)-6-chloro-4-(cyclopropyl ethynyl)-1,4-dihydrogen-4-(trifluoromethyl)-2H-3,1-benzoxazine-2-ketone, the structure of which is shown as follows:

Efaviren was approved by the FDA, US for anti-human immunodeficiency virus (HIV) infection in 1998 to inhibit HIV-1 reverse transcriptase, which is the preferred drug of non-nucleoside reverse transcriptase inhibitors (NNRTI) recommended by current international AIDS treatment guidelines.
(S)-2-amino-5-chloro-α-cyclopropyl acetylene-α-trifluoromethylbenzyl alcohol is a key intermediate for the synthesis of efavirenz. At present, there are four main methods reported for synthesizing the compound.
Method 1 is a synthetic route reported in WO9845278:

Method 2 is a synthetic method reported in WO9851676:

However, alkaline reagents are used in the asymmetric synthesis step of the above two methods. Butyl lithium is used in the method 1 and diethyl zinc is used in the method 2. The two reagents are not only expensive, but also belong to high-risk chemicals, which need strict storage conditions. The industrial use is not convenient and production accidents easily occur.
Method 3 is a synthetic method reported in CN1449865A:

In method 3, diethyl zinc in the method 2 is replaced with zinc trifluoromethanesulfonate. Although the risk of production is avoided, the zinc trifluoromethanesulfonate is not easily available and the price is also expensive. Similarly, it is not suitable for industrial production.
Method 4 is a synthetic method reported in WO2009095931:

Alkaline reagents, such as sodium hydride and zinc halide, are used in method 4, instead of diethy lzinc, which can form complexes of zinc to participate in the subsequent addition reaction as well, whereas this method still requires the use of Grignard reagent of cyclopropyl magnesium chloride. As we all know, Grignard reagent is very sensitive to water. If the materials and equipment are not dry enough in the reaction process, it is likely to cause the reaction to fail, affecting product yield. Furthermore, Grignard reaction is violent, which has strict requirements to temperature and feeding velocity. Improper operation can easily lead to the reaction out of control, and even cause the consequences of a fire, thean explosion.
Therefore, there is an urgent need in the art for the improvement of synthesis and production methods to ensure the reaction route safe and under control, raw materials easy to be obtained and a high yield, suitable for industrial production.